Systemic sclerosis (scleroderma) is a disfiguring, multi-system disease of unknown etiology, which is characterized by a broad spectrum of disease manifestations with varying organ involvement. Raynaud's phenomenon, the dysregulated vascular contraction of the terminal arteries of the circulatory system, is present in almost every case. Vascular insufficiency in these patients is associated with a vasculopathy causing tissue ischemia, which is directly linked to progressive fibrosis of specific target organs, such as the skin, lung, heart, gastrointestinal tract, and kidney. Although the underlying pathophysiology of this disorder remains an enigma, the presence of anti-nuclear antibodies in scleroderma patients is nearly universal. Targets of these autoantibodies include topoisomerase 1 (Scl-70), nuclear ribonucleoproteins (nRNP), centromere, PM-Scl, and Ku. Anti-topoisomerase-1 (topo-1) autoantibodies are quite specific for scleroderma. and are present in precipitating levels in 20-40% of patients. Anti-topo 1 is associated with diffuse skin thickening, lung involvement, and the development of lung, colon, and brain cancer. Scleroderma patients with anti-nRNP autoantibodies may have a more cutaneous form of the disease and universally suffer from Raynaud's phenomenon. Over the past decade we have extensively characterized the immunochemistry of lupus autoantigens. These previous studies provide the technical background for this proposal. Epitope mapping experiments of the lupus spliceosomal autoantigens have led to a peptide induced model of lupus autoimmunity. These studies have identified a potential etiological trigger and pathogenic mechanisms. We will now apply these well-honed techniques, as well as a similar scientific strategy, to analyze the humoral fine specificity of the anti-nRNP and anti-topoisomerase autoantibodies found in scleroderma. Preliminary data suggest a dramatic difference in the anti-nRNP response of SLE patients and scleroderma patients with nRNP autoantibodies. This project seeks to identify the common humoral epitopes of nRNP and topoisomerase-1 in scleroderma and primary Raynaud's, to describe the development of these humoral autoimmune responses over time (and with therapy), to establish potential etiological triggers of these rheumatic diseases, and to understand the role of these specific autoantibodies in scleroderma, disease pathogenesis.